Among the various phosphonate derivatives known in the art are the bisphosphonates (previously known as diphosphonates) which are structurally characterized by two C--P bonds. The simplest bisphosphonate, 1,1-(methylene)-bisphosphonate or geminal bisphosphonate (gem-bisphosphonate), is a carbon surrogate of pyrophosphate. In general, it is believed that the mode of action of the bisphosphonates in vivo is analogous to the complexing ability of pyrophosphate. However, the correspondence between complexing ability and spatial relationships of the phosphonic acids has received less attention. In general, the complexing capabilities, the inhibition of crystal growth in vitro, and tissue calcification effects in vivo are considered to decline with increasing, separation of the phosphonate groups. See H. Fleisch, Bone 8, (1987) Suppl. 1, S 23; X. Lu et al., Synthesis, (1989) 848, and G. Sturtz et al., J. Chem. Res. (S), (1978) 89.
The 1,1 class of bisphosphonates have demonstrated considerable utility in the regulation of calcification in both industrial and domestic water installations as well as in certain human diseases. Various 1,1-bisphosphonic acids nave been demonstrated to inhibit the inflammation/arthritic process in the rat adjuvant arthritis model. These include hydroxyethylidine diphosphonate, dichloromethylene diphosphonate, aminopropylidine diphosphonate, 4-chlorophenylthiomethylene bisphosphonic acid (also known as SR 41319) and 2-(3-pyridinyl) ethylidinehydroxy diphosphonic acid (also known as NE 58095). A. Barbier et al., IUPHAR, 9th Int. Cong. of Pharmacology, London, (1984) Abstract 131, have shown that SR 41319 inhibits hydroxyapatite crystal deposition in arthritic rats. However, R. Roneucci et al., Proc. Third Int. Cong. Inflam., Paris (1984) and X. Edmonds-Alt et al., Biochem. Pharmcol., (1985) 34, 4043, report that a singular mechanism for its anti-arthritic action is unlikely as cellular and immunological events are also inhibited by the drug. The foregoing studies involve the 1,1-bisphosphonic acids or their salts as do cellular studies and most biochemical studies. A selective utility of 1,1-bisphosphonate esters has been reported by L.M. Nguyen et al., J. Med. Chem., (1987) 30, 1426 with the induction of high density lipoproteins and HDL cholesterol in vivo by geminal bisphosphonate esters but not by the corresponding hemiesters or acids. An antiarthritic utility of 1,1-bisphosphonic acids and esters has been disclosed in PCT/US90/01106, filed Mar. 8, 1990, publication No. W090/12017, October 28, 1990.
In contrast, few studies describe either chemical, biochemical, or pharmacological activities of other bisphosphonic acid derivatives. Certain 1,2-bisphosphonates have been synthesized and characterized by P. Tavs et al., Tetrahedron, (1970) 26, 5529, R.R. Irani et al. J. Phys. Chem., (1962) 66, 1349 and H. Fleisch, Bone, (1987) 8, Suppl. 1, S23 and these authors report that the complexing capabilities (Irani) as well as inhibition of crystal growth in vitro and tissue calcification (Fleisch) decline with increasing separation of the phosphonate groups. No other utilities for the 1,2-bisphosphonates have been reported.
The chemistry of the 1,3-bisphosphonates has also been reported by X. Lu et al., Synthesis, (1989) 848 and G. Sturtz et al., J. Chem. Res. (S), (1978) 89. One compound, SR 7037, a tetrabutyl ester, has been reported to have specific calcium channel inhibition properties. See, J.R. Rossier et al., J. Biol. Chem., (1989) 264, 16598.
A number of other phenyl, naphthyl, and quinoxalinyl bisphosphonic acids, and short-chain alkyl esters thereof, have also been described. The compounds are useful for spectroscopic characterization, as photo conductive compounds, as intermediates or starting materials in the synthesis of distyryl, divinyl, and diaryl benzenes, dibenzophosphepins, and isophosphindoles. Finally, certain mono- and di-N-oxides of 2,3-quinoxaline-bis(methylene)bisphosphonic acid and certain esters (--CH.sub.3, --CH.sub.2 CH.sub.3, --CH.dbd.(CH.sub.3).sub.2, --CH.dbd.CHCH.sub.2) of these acids have been reported as being investigated for bactericidal activity.
We have discovered a series of bisphosphonates and oxaphosphepins which are useful as antiinflammatory and antiarthritic agents. The bisphosphonate series of compounds include phenyl, naphthyl, quinoxalinyl, and biphenyl bisphosphonic acids, esters, and salts thereof. Also disclosed is a series of novel oxaphosphepin compounds.